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Buffalo, NY 14214
Oropharyngeal candidiasis (OPC), caused by Candida albicans, is a frequent opportunistic disease in patients receiving cancer chemotherapy, AIDS patients, diabetics, and in many elderly groups especially those using oral prostheses. Alteration of the quantity and quality of saliva, especially reduction in antifungal peptides or changes in levels of human ß-defensins (hBDs), are underlying factors in development of oral candidiasis (picture).
AIDS patients, who lack CD4+ T cells are highly susceptible to OPC, indicating that these cells are critically important for immunity to Candida in the oral mucosa. Although immunity to OPC has long been thought to involve Th1 cells, mice lacking the Th1 signature cytokine IFN? are resistant to this disease. We recently reported (Conti et al., 2009), that the newly described Th17 subset of T cells is absolutely required for effective host defense against OPC. Mice deficient in Th17 cells or in the receptor for IL-17 develop fungal lesions on the tongue, palate and buccal mucosa following exposure to Candida that resembles the human clinical appearance of OPC.
The Edgerton lab and Gaffen lab (University of Pittsburgh) are collaborating to explore whether administration of anti-microbial factors can be used as an effective treatment of OPC, and to develop a mouse model by which T cell responses can be visualized and tracked during infection.
Histatins are a family of histidine-rich cationic proteins secreted by the major salivary glands in humans and higher primates that significantly contribute to the antifungal activity of saliva (hst 5 pred struct pict). Histatin 5 (Hst 5) is strongly fungicidal by causing selective loss of intracellular ions and ATP from C. albicans. Bleeding of cellular ions results in reduction of cell volume which is a hallmark of osmotically-induced cell death. HBDs share some similarities in fungicidal pathways with Hst 5, but their precise mechanism of toxicity is not known.
The research areas of the Edgerton lab are to define key elements required for Hst 5 and hBD toxicity focused on fungal cell uptake and adaptive responses. This approach may lead to alternative peptide-based therapies for treatment of oral candidiasis, which is currently limited to a small group of antifungal drugs. Ongoing projects in the Edgerton lab are to:
1. Identify transport mechanisms by which Hst 5 and hBD enter C. albicans cells. Cytotoxicity of Hst 5 is initiated upon reaching the cytosolic of C. albicans. Intracellular peptide transport is the rate limiting step for fungicidal activity, therefore defining the molecular identity of the transport mechanism is crucial.
We have identified and mapped Hst 5-binding sites of Candidal Ssa2 proteins that are necessary chaperone proteins for localization and intracelluar transport of Hst 5 into target yeast cells. A major objective of our lab is to identify central transport mechanisms of Hst 5 and other antimicrobial proteins.
2. Determine critical binding and uptake elements for cationic peptides. We have found that disruption of initial binding of Hst 5 to the yeast cell wall surface by extracelluar salts prevents fungicidal activity, and is therefore a significant barrier to use of Hst 5 or other related cationic peptides as antifungal drugs.
Thus, design of salt-insenstive peptides which are efficiently transported into the cell is essential in order to develop peptide-based therapeutic agents for candidiasis. Our lab investigates critical amino acids motifs required for Hst 5 activity as well as other antimicrobial peptides.
3. Identify Candidal stress response mechanisms involved in resistance to cationic peptides. We have identified the C. albicans Hog1 MAPKinase pathway to be an important response mechanism for recovery of cells from osmotic stress induced by Hst 5. Candidal cells in the oral environment exposed to low physiological levels of antifungal peptides may develop resistance through constitutive activation of Hog1p. Therefore, understanding these response pathways and their initiating sensors will guide therapies to overcome Candidal adaptive resistance. Our lab focuses on understanding the cellular mechanisms of C. albicans membrane sensors Sho1 and Sln1 in mediating stress response induced by Hst 5 through activation of Hog1 MAP Kinase pathways.